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Review
. 2025 Aug;12(30):e02714.
doi: 10.1002/advs.202502714. Epub 2025 Jun 9.

Mechanistic Foundations of KRAS-Driven Tumor Ecosystems: Integrating Crosstalk among Immune, Metabolic, Microbial, and Stromal Microenvironment

Jiayao Ma  1 , Shenao Fu  1 , Jun Tan  2   3 , Ying Han  1   3 , Yihong Chen  1   3 , Xiangying Deng  1   3 , Hong Shen  1   3 , Shan Zeng  1   3 , Yinghui Peng  1 , Changjing Cai  1   3
Affiliations
Review

Mechanistic Foundations of KRAS-Driven Tumor Ecosystems: Integrating Crosstalk among Immune, Metabolic, Microbial, and Stromal Microenvironment

Jiayao Ma et al. Adv Sci (Weinh). 2025 Aug.

Abstract

Kirsten rat sarcoma viral oncogene homolog (KRAS) is the most frequently mutated member of the RAS family of small GTPases (RAS). It affects about one-fifth of cancer cases. The tumor microenvironment (TME) is a multifaceted network of immune cells, metabolites, microbiota, stromal components, and extracellular matrix. It creates a dynamic ecosystem that supports malignant initiation, progression, and therapy resistance through bidirectional crosstalk with tumor cells. Emerging evidence reveals distinct TME landscapes shaped by wild-type versus oncogenic KRAS variants. Additionally, TME rewiring occurs during KRAS-targeted therapies. Deciphering these KRAS-dependent TME architectures and their therapeutic vulnerabilities represents a critical frontier for precision oncology. This review synthesizes key milestones and persistent challenges in KRAS inhibitor development. And it systematically evaluates how KRAS mutations orchestrated immunosuppressive niches, metabolic symbiosis, stromal remodeling, and microbiome dysbiosis, supported by mechanistic insights from preclinical and clinical studies. It further explores therapeutic opportunities arising from targeting TME interactions, including rational combinations of KRAS inhibitors with immune checkpoint blockade, metabolic agents, or microbiota-modulating strategies.

Keywords: KRAS; cancer; immunity; metabolism; microbiota; microenvironment; stroma.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
The prevalence of RAS mutations and the target range of KRAS/RAS inhibitors/degraders.
Figure 2
Figure 2
The milestones achieved in KRAS drug development and ongoing challenges in the development of KRAS inhibitors.
Figure 3
Figure 3
Alterations in the tumor immune microenvironment induced by oncogenic KRAS mutations.
Figure 4
Figure 4
Alterations in the tumor metabolic and stromal microenvironment induced by oncogenic KRAS mutations.
Figure 5
Figure 5
The tumor microbial microenvironment associated with oncogenic KRAS mutations.
Figure 6
Figure 6
The crosstalk among tumor microenvironment residents in KRAS mutant tumors.
Figure 7
Figure 7
Overview of the tumor microenvironment regulation strategies in KRAS mutant tumors.
See this image and copyright information in PMC

References

    1. Prior I. A., Hood F. E., Hartley J. L., Cancer Res. 2020, 80, 2969. - PMC - PubMed
    1. a) Scharpf R. B., Balan A., Ricciuti B., Fiksel J., Cherry C., Wang C., Lenoue‐Newton M. L., Rizvi H. A., White J. R., Baras A. S., Anaya J., Landon B. V., Majcherska‐Agrawal M., Ghanem P., Lee J., Raskin L., Park A. S., Tu H., Hsu H., Arbour K. C., Awad M. M., Riely G. J., Lovly C. M., Anagnostou V., Cancer Res. 2022, 82, 4058; - PMC - PubMed
    2. b) Lee J. K., Sivakumar S., Schrock A. B., Madison R., Fabrizio D., Gjoerup O., Ross J. S., Frampton G. M., Napalkov P., Montesion M., Schutzman J. L., Ye X., Hegde P. S., Nagasaka M., Oxnard G. R., Sokol E. S., Ou S. I., Shi Z., NPJ Precis. Oncol. 2022, 6, 91. - PMC - PubMed
    1. a) Settleman J., Albright C. F., Foster L. C., Weinberg R. A., Nature 1992, 359, 153; - PubMed
    2. b) Scheffzek K., Ahmadian M. R., Kabsch W., Wiesmüller L., Lautwein A., Schmitz F., Wittinghofer A., Science 1997, 277, 333. - PubMed
    1. Boriack‐Sjodin P. A., Margarit S. M., Bar‐Sagi D., Kuriyan J., Nature 1998, 394, 337. - PubMed
    1. a) Waters A. M., Der C. J., Cold Spring Harb. Perspect. Med. 2018, 8, a031435; - PMC - PubMed
    2. b) Bos J. L., Rehmann H., Wittinghofer A., Cell 2007, 129, 865. - PubMed

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